Organic compounds that are charged at physiological pH frequently exhibit limited oral bioavailability, cell penetration, and tissue distribution (e.g. CNS). These properties are attributed to the failure of ionic compounds to cross cell membranes by passive diffusion. One strategy to circumvent this problem is to prepare lipophilic prodrugs which are capable of crossing cell membranes and subsequently undergoing a transformation to generate the charged compound. The transformation could result from either chemical instability or an enzyme-catalyzed reaction.
A large number of structurally-diverse prodrugs are described for phosphonic acids. Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997). The most commonly used prodrug class is the acyloxyalkyl ester, which was first used as a prodrug strategy for carboxylic acids and then applied to phosphates in 1983 by Farquhar et al. J. Pharm. Sci. 72: 324 (1983). Subsequently, the acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability. A close variant of the acyloxyalkyl ester strategy, the alkoxycarbonyloxyalkyl ester, is also reported to enhance oral bioavailability.
Much less success has been achieved with other classes of phosphonate prodrugs. Aryl esters, especially phenyl esters, are reported in a few cases to enhance oral bioavailability. DeLambert et al., J. Med. Chem. 37: 498 (1994). Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described. Khamnei and Torrence, J. Med. Chem. 39:4109-4115 (1996). Benzyl esters are reported to generate the parent phosphonic acid. In some cases using substituents at the ortho- or para-position can accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol can generate the phenolic compound through the action of enzymes, e.g. esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic C—O bond to generate the phosphoric acid and the quinone methide intermediate. Examples of this class of prodrugs are described by Mitchell et al., J. Chem. Soc. Perkin Trans. I 2345 (1992); Brook, et al. WO 91/19721. Still other benzylic prodrugs have been described containing a carboxylic ester-containing group attached to the benzylic methylene. Glazier et al. WO 91/19721. Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide. Desterification or reduction of the disulfide generates the free thio intermediate which subsequently breaks down to the phosphoric acid and episulfide. Puech et al., Antiviral Res., 22: 155-174 (1993); Benzaria, et al., J. Med. Chem. 39: 4958 (1996). Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds.
Some phosphoramidates are also known prodrugs of phosphonates, but they have shown poor oral bioavailability. In some cases the phosphoramidates were very unstable under acidic conditions which was reported as a potential explanation for their poor oral bioavailability (J. Med. Chem., 37: 1857-1864 (1994)). Similarly, poor oral bioavailability was reported for a bisamidate of a PMEA analog (J. Med. Chem., 38: 1372-1379 (1995)). Another PMEA prodrug consists of a mono glycine ester amidate and a phenyl ester (WO 95/07920).
Although numerous phosphoric acid prodrug strategies are reported to achieve high intracellular delivery of phosphoric acids, few are known to result in good oral bioavailability. In some cases, the prodrugs are unstable to the gastrointestinal tract environment (low pH, esterase activity). In other cases the prodrugs are too stable and are therefore poorly transformed in vivo to the parent drug.
WO 98/39344, WO 98/39343, WO 98/139342, and WO 00/14095 describe compounds containing phosphoric acids and esters that inhibit fructose-1,6-bisphosphatase.
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